Project Summary The overall goal of this proposal is to develop and implement novel, multi-modal, quantitative magnetic resonance imaging (MRI) in the human spinal cord (SC) at clinical field strengths (3T) to quantitatively assess the relationship between SC pathology and neurological deficit in multiple sclerosis (MS). We propose that quantitative MRI methods sensitive to tissue microstructure (myelin) and biochemistry can be developed to be sensitive to sub-voxel pathology that is present in MS. However, the SC is a challenging environment from which to obtain high-resolution, quantitative MRI data. Importantly, advanced MRI methods have mainly been developed to assess large structures of central nervous system and relatively few have been applied in the SC due to its size, location, and motion. Yet it is imperative that we embark on this study as it has been hypothesized that the bulk of clinical deficit in MS comes as a result of lesions in the SC rather than the brain. In fact, a clinical radiological paradox exists in that the neurological presentatin in patients with MS does not always match the severity of radiological findings. We propose that this is due to the lack of quantitative and sensitive markers for the magnitude of damage that the SC experiences. Secondly, since the spinal cord is somatotopically organized, if sufficient quality MRI data are obtained, we can directly probe the structure- function relationship. We propose to develop, implement and evaluate two quantitative MRI measures of the health of the SC, neither of which have been developed for the SC at 3T. First, we will develop a high- resolution, rapid, multi- and single-point quantitative magnetization transfer (qMT) experiment to derive the pool size ratio (PSR), which has been shown to be directly correlated with myelin density. Secondly, we have shown that amide proton transfer (APT) - chemical exchange saturation transfer (CEST) is sensitive to the earliest changes in normal appearing white matter at high field. Nevertheless, for this to be clinically viable, it must be transitioned to lower fied and applied to the SC. Thus, we propose to develop and implement high- resolution, robust APT-CEST in the SC to assess the changes that may occur in lesions and in otherwise normal appearing white matter. Together, the success of this proposal will be determined by the development, validation, and application of two novel MRI measures to the cervical SC of patients with MS with the potential pay-off being sensitivity to late-stage MS pathology (i.e. demyelination from qMT) and potentially early stage MS pathology (i.e. protein accumulation from CEST). If successful, we will also have developed and validated a SC toolbox to quantitatively assess myelin changes, protein (and pH) changes in a variety of diseases that affect the SC. It should not go with out notice that extensions to the optic nerve, peripheral nerves, and thoracic/lumbar spinal cord are well within the scope of the results of this proposal.